This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. According to the National Survey on Drug Use and Health over 10 million people have tried the club drug "Ecstasy" (MDMA) at least once in their lifetime. Currrently there are no therapeutically specific agents to treat MDMA addiction and overdose. The natural product (+)-nantenine has been found to antagonize some of the effects of MDMA in vivo and shows promise for the deveopment of well-needed MDMA therapeutics. The long-term goal of this project is to develop therapeutic agents based on nantenine to treat MDMA dependence and overdose. The objective of this exploratory application is to better understand the role of various structural motifs of (+)-nantenine for antagonism of the physiological and behavioral effects of MDMA in mice. The Central Hypothesis of this proposal is that structural modification of nantenine will lead to potent molecules with the ability to antagonize behavioral and physiological effects induced by MDMA in vivo. The rationale of this application is that an understanding of the role/importance of various structural motifs of nantenine on MDMA antagonistic activity in vivo, will provide valuable information for the development of novel therapeutic agents to treat MDMA dependence and overdose based on the (+)-nantenine core structure. We plan to test the central hypothesis and achieve the overall objectives by pursuing the following specific aims: Specific Aim #1: Examine the importance of the chiral center of nantenine in blocking and/or reversing MDMA-induced effects in mice. The working hypothesis of this specific aim is that the chiral center of nantenine is important for in vivo antagonism of MDMA's behavioral and physiological effects. Specific Aim #2: Examine the role of the C-2 site of the (+)-nantenine aporphine core on MDMA-induced behavioral and physiological effects in mice. The working hypothesis of this aim is that the C-2 position of the (+)-nantenine aporphine core is a crucial site for modulation of its MDMA antagonizing effects in vivo. We will chemically synthesize analogs of nantenine and evaluate the ability of the analogs to block/reverse MDMA-induced effects in mice. The completion of this project will allow us to determine structure-activity relationships of nantenine in relation to in vivo MDMA antagonism and lead to the design of potent therapeutics to treat MDMA addiction and overdose.